Many researchers have utilized hot-melt extrusion techniques to produce pharmaceutical preparations in various forms. Zhang and McGinity utilized hot-melt extrusion to produce sustained release matrix tablets with PEO and polyvinyl acetate, and more generally non-film preparations with polyethylene oxide (PEO) (1-3). Kothrade et al. demonstrated a method of producing solid dosage forms of active ingredients in a vinyllactam co-polymeric binder by hot-melt extrusion (4). Aitken-Nichol et al. used hot-melt extrusion methods to produce acrylic polymer films containing the active lidocaine HCl (5). Grabowski et al. produced solid pharmaceutical preparations of actives in low-substituted hydroxypropyl cellulose using hot-melt extrusion techniques (6). Repka and McGinity used hot-melt extrusion processes to produce bioadhesive films for topical and mucosal adhesion applications for controlled drug delivery to various mucosal sites (7, 8). Robinson et al. produced effervescent granules with controlled rate of effervescence using hot melt extrusion techniques (3). Breitenbach and Zettler produced solid spherical materials containing biologically active substances via hot-melt extrusion (9). De Brabander et al. demonstrated sustained release mini-matrices by utilizing hot-melt extrusion techniques (10, 11).
Pharmaceutical formulations comprised of active compounds finely and homogenously dispersed in one or more polymeric carriers have been described as solid dispersions, glass solutions, molecular dispersions, and solid solutions. The term solid dispersion has been used as a general term to describe pharmaceutical preparations in which the active compound is dispersed in an inert excipient carrier in a size range from course to fine. Glass solution, molecular dispersion, and solid solution refer specifically to preparations in which amorphous forms of a crystalline active compound are formed in-situ and dispersed within the polymer matrix during the hot-melt extrusion process.
Many researchers have produced such preparations with various active compounds and polymeric carriers using hot-melt extrusion techniques. Rosenberg and Breitenbach have produced solid solutions by melt extruding the active substance in a nonionic form together with a salt and a polymer, such as polyvinylpyrrolidone (PVP), vinylpyrrolidinone/vinylacetate (PVPVA) copolymer, or a hydroxyalkylcellulose (12). Six et al., Brewster et al., Baert et al., and Verreck et al. have produced solid dispersions of itraconazole with improved dissolution rates by hot-melt extrusion with various polymeric carriers including hydroxypropylmethylcellulose, Eudragit E100, PVPVA, and a combination of Eudragit E100 and PVPVA (13-19). Rambaldi et al. produced solid dispersions of itraconazole by hot-melt extrusion with hydroxypropyl-beta-cyclodextrin and hydroxypropylmethylcellulose for the improvement of aqueous solubility (20). Verreck et al. produced solid dispersions of a water-insoluble microsomal triglyceride transfer protein inhibitor with improved bioavailability by hot-melt extrusion (21). Hulsmann et al. produced solid dispersions of the poorly water soluble drug 17 β-estradiol with increased dissolution rate by hot melt extrusion with polymeric carriers such as polyethylene glycol, PVP, and PVPVA along with various non-polymeric additives (22). Forster et al. produced amorphous glass solutions with the poorly water soluble drugs indomethacin, lacidipine, nifedipine, and tolbutamide in PVP and PVPVA demonstrating improved dissolution compared with the crystalline forms (23). In this article, it is also seen that after storage of the extrudates at 25° C. and 75% relative humidity only compositions containing indomethacin and polymer in a one to one ratio remained completely amorphous. Formulations of the remaining drugs and formulations with increased indomethacin concentration showed recrystallization on storage. This recrystallization was shown to significantly decrease the dissolution rate of the active. It should also be noted that stability studies were not performed at elevated temperatures in this study. It would be expected that elevated temperatures would increase the occurrence and extent of recrystallization.
The previous reference reveals the inherent instability of amorphous dispersions produced by hot-melt extrusion techniques. Although many articles demonstrate the production of amorphous solid dispersions and the resulting improvement of drug dissolution rate, very few discuss the stability of such preparations on storage. From the work of Foster et al. and an understanding of the thermodynamics of amorphous systems, it can be concluded that recrystallization of amorphous solid dispersion formulations on storage is a common problem. The amorphous state is thermodynamically metastable, and therefore it is expected that amorphous compounds will assume a stable crystalline conformation with time, as well as in response to perturbations such as elevations in temperature and exposure to moisture. In an extruded formulation, amorphous drug particles will agglomerate and crystallize with increasing storage time, elevated temperature, or exposure to moisture, essentially precipitating out of the carrier. This progression towards phase separation during storage results in a time dependant dissolution profile. A change in dissolution rate with time precludes the successful commercialization of a pharmaceutical product.
The article by Foster et al. also demonstrates the limitation of drug loading in amorphous solid dispersions by hot-melt extrusion. It is seen in this article that recrystallization of indomethacin on storage is induced when the concentration of indomethacin is increased from 1:1 to 4:1 drug to polymer ratio. Six et al. demonstrated immiscibility of itraconazole and Eudragit E100 when extruded at 140° C. and phase separation on processing at concentrations greater than 13% and 20% (w/w) when extruded at 168° C. and 180° C., respectively (14-16). Six et al. also demonstrated a single phase system of itraconazole and PVPVA at drug concentrations up to 80% (w/w), however only a slight improvement of the dissolution rate was achieved (16). Kearney et al. showed phase separation of an anti-inflammatory drug, CI-987, in PVP at drug concentrations greater than 19% (w/w) for solid dispersions prepared by solvent evaporation methods (24). Verreck et al. demonstrated an amorphous dispersion of itraconazole in HPMC at a concentration of 40% drug, with improved dissolution rate and chemical and physical stability for up to 6 months at various temperature and humidity conditions (17). In a follow up article, Six et al. showed phase separation of itraconazole from identical HPMC carrier systems at a concentration of 60% drug (13).
The difficulty of producing stable single phase amorphous dispersions of high drug loading can be seen from references such as those given above. The appearance of a second phase of the active compound on processing or on storage would result in a time dependent biphasic dissolution profile, and would therefore not be considered an acceptable pharmaceutical preparation.
Although there have been many reports of successful production of solid dispersions by hot-melt extrusion that show improved dissolution rates of poorly water soluble drugs, the absence of numerous marketed products based on this technology is evidence that stability problems remain a major obstacle for successful commercialization of such a pharmaceutical preparation.
There are several methods well known in the pharmaceutical literature for producing fine drug particles in the micro or nanometer size range. These methods can be divided into three primary categories: (1) mechanical micronization (2) solution based phase separation and (3) rapid freezing techniques.
Mechanical micronization is most commonly done by milling techniques that can produce particles in the range of 1 to 20 microns. The most common processes utilized for this type of mechanical particle size reduction are ball and jet milling. Milling drug particles by these processes can reduce primary drug particles to micron-sized particles, however high surface energy results in aggregation of primary particles which to an extent negates the milling process. Nykamp et al. and Carstensen et al. demonstrated a melt grinding and jet milling technique to produce drug loaded microparticles of polylactic acid or polylactic-co-glycolic acid with mean particle size in the range of four to six microns (25, 26).
There are many solution based phase separation processes documented in the pharmaceutical literature for producing micro and nano-sized drug particles. Some of the more commonly known processes are spray drying, emulsification/evaporation, emulsification/solvent extraction, and complex coacervation. Some of the lesser-known processes are, for the sake of brevity, listed below along with their respective illustrating references: a) gas antisolvent precipitation (GAS)—(27) and WO9003782 EP0437451 EP0437451 DK59091; b) precipitation with a compressed antisolvent (PCA)—(28) and U.S. Pat. No. 5,874,029; c) aerosol solvent extraction system (ASES)—(29); d) evaporative precipitation into aqueous solution (EPAS)—(30) US patent application 20040067251; e) supercritical antisolvent (SAS)—(31); f) solution-enhanced dispersion by supercritical fluids (SEDS)—(32); g) rapid expansion from supercritical to aqueous solutions (RESAS)—(33); and h) anti-solvent precipitation.
Freezing techniques for producing micro or nano-sized drug particles are listed below along with their respective illustrating references: a) spray freezing into liquid (SFL)—(34) WO02060411 USPTO App. #2003054042 and 2003024424; and b) ultra rapid freezing (URF)—(35).
It should be noted that fine drug particles produced by solution-based phase separation or rapid freezing techniques are often amorphous in nature. Theses amorphous particles can be stabilized by complexation or coating during the production process with one or more excipient carriers having high melting points or glass transition temperatures. Stabilized amorphous fine drug particles can be formulated into the present preparation in the same manner as crystalline fine drug particles. The high shear of the hot-melt extrusion process will effectively deaggregate and disperse the amorphous drug particles (likely to be aggregated before extrusion due to high surface energy as stated in the next paragraph) into the stabilizing and non-solubilizing carrier thereby separating the aggregated particles into primary particles that are stabilized against aggregation and agglomeration on processing and storage by the carrier system. The excipient system with which the amorphous drug particles are complexed or coated will prevent recrystallization during hot-melt extrusion and storage of the amorphous drug-containing particle domains that are dispersed in the stabilizing and non-solubilizing carrier matrix. The benefit of this form of an amorphous dispersion compared to a traditional amorphous dispersion is that the formation of fine amorphous drug particles is not dependent on the solubility of the drug in the carrier system, since the amorphous drug particles are not formed in situ by the solubilization of the crystalline drug particles by the carrier system.
It has been reported that fine drug particles produced by processes such as those listed above exhibit high surface energy resulting in strong cohesive forces between particles. Zimon showed that powders of fine particles are likely to aggregate because the force of detachment is dependent on particle mass which is small in the case of fine particles (36). The forces of cohesion between individual fine particles are therefore greater than the forces of detachment, and thus particle aggregates form. French et al. demonstrated that the forces of cohesion between particles increase with decreasing particle size (37). Therefore, the extent of aggregation is increased as particle size is reduced.
Aggregation of fine particles results in an increase in the apparent particle size, consequently, particle size reduction is somewhat negated. In order to achieve the full benefit of particle size reduction, i.e. accelerated dissolution rate, aggregates must be reduced to individual particles when dosed. Lui and Stewart demonstrated a reduction in dissolution rate of benzodiazepines with an increasing extent of particle aggregation (38).
Particle agglomeration with storage also causes an increase in apparent particle size, and a corresponding decrease in dissolution rate. Ticehurst et al. demonstrated agglomeration of micronized revatropate hydrobromide when stored at greater than 25% relative humidity (39). Therefore, in the production of an ideal solid dosage form containing fine drug particles, aggregates would be separated and stabilized as individual particles by a carrier system during processing. The carrier system would also function to impede particle aggregation and agglomeration on storage at ambient and accelerated temperature and humidity conditions.
There have been few published reports of the successful incorporation of fine drug particles into a traditional dosage forms. Hu et al. developed an immediate release tablet of Danazol micronized powder by the SFL process, however only 5.3% drug loading was reported (40). Authors have also reported on the oral delivery of fine drug particles in the form of a stabilized liquid suspension (41, 42). There are two important limitations of delivering fine drug particle formulations in a liquid suspension, namely the instability of the preparation and the commercial limitation of shipping suspensions. Liquid suspensions are known to be unstable on storage due to agglomeration, and sedimentation, as well as caking of suspended particles. Commercially it is not ideal to formulate a pharmaceutical preparation as a suspension due to the cost of shipping the excess weight of the liquid vehicle, as compared to a solid dosage form.
Prior art examples such as those given above demonstrate the ongoing need for the advantageous properties of the present invention for the delivery of drug from a hot-melt extruded composition comprising fine drug particles.